A structural analysis of the differential cytotoxicity of chemicals in the NCI-60 cancer cell lines.

The primary functions of cancer chemotherapeutic agents are not only to inhibit the growth or kill the cancer cells, but to do so without eliciting unreasonable cytotoxic effects on the healthy cells and to withstand the ability of the cancer cells to develop resistance against it. This has unfortunately been proven so far to be a very difficult objective. In this perspective, the ability of small molecules (anti-tumor agents) to 'see' different cell types differently can be a key attribute. Thus the term 'differential cytotoxicity' is normally used to describe the drug's specificity. In the present paper, we have quantified differential cytotoxicity from a study of the chemicals tested in the National Cancer Institute's Developmental Therapeutics Program. The MULTICASE (Multiple Computer Automated Structure Evaluation) methodology was used to discover statistically significant structural fragments (biophores) related to the differential cytotoxicity of the compounds. We found that even small structural features often become important in this regard which is evident from the biophores that were found in structurally diverse chemicals. By utilizing the difference between the raw and normalized differential cytotoxicity indices, we found that the alpha,beta-unsaturated carbonyl group (O=C-C=CH(2)) is the major biophore associated with compounds with essentially parallel concentration profiles in the cell lines in question. These compounds have high non-normalized differential cytotoxicity but considerably low normalized differential cytotoxocity. The models developed were cross validated for their predictive ability.